Phenotypes Associated with This Genotype

Genotype
MGI:8203535

• Allelic Composition: Nwd1^em2.1Sisa/Nwd1^em2.1Sisa
• Genetic Background: involves: C57BL/6 * C57BL/6N * DBA/2

• ♀: phenotype observed in females
• ♂: phenotype observed in males
• N: normal phenotype

mortality/aging

increased susceptibility to xenobiotic induced morbidity/mortality ( J:363603 )

• 40% of mice administered tunicamycin die within 48 hours, indicating that mice are more vulnerable to ER stress or that the basal level of ER stress was elevated in the livers

prenatal lethality, incomplete penetrance ( J:363603 )

• birth rate of homozygotes is 7% lower than expected from the Mendelian ratio

liver/biliary system

abnormal Kupffer cell morphology ( J:363603 )

• macrophages in liver are hypertrophied, characterized by a swollen cytoplasm and irregular ameboid morphology, suggesting the activation of resident Kupffer cells in the liver

• however, no difference in the mean number of Kupffer cells is seen in the liver

enlarged liver ( J:363603 )

• livers show an approximate 1.4-fold increase in liver size despite no difference in body weight

increased liver cholesterol level ( J:363603 )

• liver shows a higher accumulation of total cholesterol

• however, total content of triglycerides and cholesterol in the peripheral serum is unchanged

increased liver triglyceride level ( J:363603 )

abnormal hepatocyte morphology ( J:363603 )

• liver shows an increase in the number of enlarged and lucent hepatocytes; these swollen hepatocytes do not appear to have undergone programmed cell death

• PAS staining, detecting glycogen and mucosubstances such as glycoproteins and mucins, is reduced in swollen hepatocytes

• hepatocytes contain many vacant vacuoles in addition to lipid droplets filled with triglycerides

• the numbers of giant lipid droplets and large vacuoles are increased in hepatocytes

• vacuoles in hepatocytes are derived from the endoplasmic reticulum (ER)

hepatic steatosis ( J:363603 )

• liver shows abnormal speckled fatty-like patterns and an increase in neutral lipid content in hepatocytes

• many lipid droplets, storage organelles for neutral lipids, accumulate in a zonate pattern around the central vein in the hepatic lobule

liver fibrosis ( J:363603 )

• liver shows white fibrotic-like structures on the surface of hepatic lobes

• severe collagen fiber deposition in the liver indicating fibrosis that resembles metabolic dysfunction-associated steatohepatitis (MASH)

• however, livers do not accumulate amyloid fibrils

abnormal liver physiology ( J:363603 )

• despite an increase in cholesterol and triglyceride levels in the liver, mice exhibit nearly identical rates of increase in peripheral blood triglycerides and total cholesterol following Triton WR-1339 administration, suggesting that clearance of accumulated lipid droplets is suppressed in the liver

• further, lipid droplets in the liver are rarely observed in the sinusoids indicating that mice have defective lipid droplet efflux from the sinusoids

• calcium stores in liver endoplasmic reticulum are depleted by about 40%, however, the amount of calcium in liver mitochondria is not different

• liver shows elevated ER stress

cardiovascular system

abnormal Kupffer cell morphology ( J:363603 )

• macrophages in liver are hypertrophied, characterized by a swollen cytoplasm and irregular ameboid morphology, suggesting the activation of resident Kupffer cells in the liver

• however, no difference in the mean number of Kupffer cells is seen in the liver

cellular

increased pyroptosis ( J:363603 )

• livers show accelerated inflammatory pyroptosis

• however, livers do not show increased apoptosis as hepatocytes lack nuclear fragmentation

increased endoplasmic reticulum stress ( J:363603 )

• liver shows elevated endoplasmic reticulum (ER) stress

growth/size/body

enlarged liver ( J:363603 )

• livers show an approximate 1.4-fold increase in liver size despite no difference in body weight

hematopoietic system

abnormal Kupffer cell morphology ( J:363603 )

• macrophages in liver are hypertrophied, characterized by a swollen cytoplasm and irregular ameboid morphology, suggesting the activation of resident Kupffer cells in the liver

• however, no difference in the mean number of Kupffer cells is seen in the liver

increased leukocyte cell number ( J:363603 )

• total number of leukocytes is 3-fold higher

• although mice have increased counts of each type of leukocytes, including monocytes, lymphocytes, neutrophils, eosinophils, and basophils, the proportion of each cell type is unchanged

homeostasis/metabolism

increased liver cholesterol level ( J:363603 )

• liver shows a higher accumulation of total cholesterol

• however, total content of triglycerides and cholesterol in the peripheral serum is unchanged

increased liver triglyceride level ( J:363603 )

increased susceptibility to xenobiotic induced morbidity/mortality ( J:363603 )

• 40% of mice administered tunicamycin die within 48 hours, indicating that mice are more vulnerable to ER stress or that the basal level of ER stress was elevated in the livers

immune system

abnormal Kupffer cell morphology ( J:363603 )

• macrophages in liver are hypertrophied, characterized by a swollen cytoplasm and irregular ameboid morphology, suggesting the activation of resident Kupffer cells in the liver

• however, no difference in the mean number of Kupffer cells is seen in the liver

increased leukocyte cell number ( J:363603 )

• total number of leukocytes is 3-fold higher

• although mice have increased counts of each type of leukocytes, including monocytes, lymphocytes, neutrophils, eosinophils, and basophils, the proportion of each cell type is unchanged

respiratory system

abnormal pulmonary alveolus morphology ( J:363603 )

• lungs exhibit flattened alveoli

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
metabolic dysfunction-associated steatohepatitis		DOID:0080547		J:363603